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Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders 7. Anti-Inflammatory and Antioxidant Activity The mechanism of action of NAC as an anti-inflammatory is complex and involves both antioxidant activity and reestablishment of redox equilibrium (figure 9). [7,14] Oxidants and free radical attack cause inflammatory damage (section 3); therefore, agents with antioxidant activity, such as NAC, will inhibit the inflammatory process. NAC not only acts directly as an antioxidant, but also has indirect antioxidant properties as it is a precursor to biosynthesis of the antioxidant glutathione (figure 10). [7,16] Pulmonary tissues have a variety of both intracellular and extracellular antioxidant defense systems in order to counterbalance the production of free radicals and cope with the normal oxidative burden within the lungs. Antioxidant defense systems include antioxidant molecules and enzymatic systems, the most important of which is glutathione and its related complex enzymatic systems. [7,12,24] Glutathione directly detoxifies reactive species by conjugation and/or reduction; the enzyme systems enhance chemical detoxification by catalyzing conjugation reactions and reductions. [16] Glutathione has also been implicated in numerous cellular functions. [12,14] Inflammation is mediated by inducible transcription factors that switch on the genes for inflammatory proteins. Reactive species activate this transcription, leading to the release of proinflammatory cytokines. [7] Therefore, to neutralize reactive species and prevent activation of transcription of inflammatory protein genes, the cellular redox equilibrium between reduced glutathione and its oxidized species glutathione disulfide must be maintained (figure 10). [7,14] It is essential to maintain adequate intracellular levels of glutathione to overcome the harmful effects of reactive species. Depletion of glutathione is caused by its antioxidant activity and also by elimination of oxidized glutathione from the cells. Once oxidized glutathione is eliminated from the cell, it is not available to be regenerated to reduced glutathione via the reductase pathway. The rate-limiting substrate in the synthesis of glutathione is cysteine. [7,12,24] Cysteine is difficult to administer as it is poorly absorbed, has low solubility in Fig. 9 Pathway showing the mechanism of action of N-acetylcysteine (NAC) as an antioxidant and reestablisher of reductiveoxidative (redox) equilibrium in the presence of oxidative stress. Oxygen- and nitrogen-free radicals produced Oxidative stress NAC Increases intracellular and extracellular antioxidant defenses Re-establishes cellular redox equilibrium Controls activation of transcription of inflammatory genes Prevents lipid peroxidation and cell membrane damage Prevents inflammation of airways and lungs Controls release of proinflammatory cytokines 13
Current <strong>Therapeutics</strong> water and undergoes rapid hepatic metabolism. [14] However, additional cysteine may be delivered by the administration of NAC because it is a precursor to cysteine (figure 10). NAC increases the endogenous supply of cysteine, either by deacetylation of NAC or through reduction by NAC of endogenous cystine into cysteine. [16] Relative to cysteine, NAC is well absorbed intestinally, has good water solubility, is stable to oxidation and is well tolerated. Administration of NAC results in increased levels of endogenous cysteine that: • stimulate glutathione synthesis when there is an increased demand • enhance the activity of enzymes dependent on glutathione • promote antioxidant activity. NAC, therefore, maintains the redox-equilibrium between reduced glutathione and oxidized glutathione and acts directly as an antioxidant, which leads to complete airway protection against oxidative stress and inflammation (figure 9). NAC inhibits the activation of some redox-sensitive signal transduction factors. [14] Therefore, NAC prevents the release of proinflammatory cytokines (figure 9) and, as a result, would have longer-term effects on the inflammatory response than agents that inhibit only the inflammation mediators involved in the last steps of the inflammatory process. [7] The anti-inflammatory and antioxidative actions of NAC have been shown in many in vitro and animal-model studies (table V). [49-60] 7.1 Patients with chronic obstructive pulmonary disease The anti-inflammatory and antioxidative actions of NAC have also been demonstrated in studies in patients with COPD (table VI). [14,16,49,50,61-68] Markers of oxidative stress and inflammation were reduced in the red blood cells, sputum and blood of these patients. [66-68] Oral NAC decreased levels of C-reactive protein, which is a marker of inflammation, in patients with acute exacerbations of COPD. [68] This double-blind 10-day study compared the efficacy of two dosage regimens of oral NAC (600 or 1200mg/day) with that of placebo in reducing the levels of C-reactive protein and other indicators of inflammation in 122 patients with an acute exacerbation of COPD. Levels of C-reactive protein decreased to a greater extent with NAC than with placebo at day 5 and day 10 of the trial (figure 11). The improvement was greater with the Fig. 10 Reductive-oxidative (redox) equilibrium between reduced glutathione and glutathione disulfide. In the presence of oxidative stress, there is a lack of sufficient reduced glutathione to neutralize the reactive species and, therefore, redox equilibrium is not maintained. N-acetylcysteine (NAC) restores redox equilibrium by increasing levels of endogenous cysteine, resulting in increased levels of glutathione. Reactive species Neutral species NAC N-acetylcysteine Cysteine Reduced glutathione Glutathione reductase Oxidized glutathione 14
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